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Increased glucocorticoid receptor expression and activity mediate the LPS resistance of SPRET/EI mice

Lien Dejager (UGent) , Iris Pinheiro (UGent) , Leen Puimège (UGent) , Yedong Fan (UGent) , Lies Gremeaux, Hugo Vankelecom and Claude Libert (UGent)
(2010) JOURNAL OF BIOLOGICAL CHEMISTRY. 285(40). p.31073-31086
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Abstract
SPRET/Ei mice are extremely resistant to acute LPS-induced lethal inflammation when compared to C57BL/6. We found that in vivo SPRET/Ei mice exhibit strongly reduced expression levels of cytokines and chemokines. To investigate the role of the potent antiinflammatory glucocorticoid receptor (GR) in the SPRET/Ei phenotype, mice were treated with the GR antagonist RU486 or bilateral adrenalectomy. Under such conditions, both C57BL/6 and SPRET/Ei mice were strongly sensitized to LPS and the differences in LPS response between SPRET/Ei and C57BL/6 mice were completely gone. These results underscore the central role of GR in the LPS hyporesponsiveness of SPRET/Ei mice. Compared to C57BL/6, SPRET/Ei mice were found to express higher GR levels, which were reflected in increased GR transactivation. Using a backcross mapping strategy, we demonstrate that the high GR transcription levels are linked to the Nr3c1 (GR) locus on chromosome 18 itself. Unexpectedly, SPRET/Ei mice exhibit a basal overactivation of the hypothalamic-pituitary-adrenal axis, namely strongly increased corticosterone levels, ACTH levels and adrenocortical size. As a consequence of the excess of circulating glucocorticoids (GCs), levels of hepatic gluconeogenic enzymes are increased and insulin secretion from pancreatic β-cells is impaired, both of which result in hyperglycemia and glucose intolerance in SPRET/Ei mice. We conclude that SPRET/Ei mice are unique since they display an unusual combination of elevated GR expression and increased endogenous GC levels. Hence, these mice provide a new and powerful tool for the study of GR- and GC-mediated mechanisms, including immune repressive functions, neuroendocrine regulation, insulin secretion, and carbohydrate metabolism.
Keywords
INSULIN, GENE, MOUSE, ENDOTOXIC-SHOCK, FEEDBACK-CONTROL, HORMONE-RECEPTORS, PANCREATIC BETA-CELLS, TUMOR-NECROSIS-FACTOR, MOLECULAR-MECHANISMS, FACTOR-KAPPA-B

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Chicago
Dejager, Lien, Iris Pinheiro, Leen Puimège, Yedong Fan, Lies Gremeaux, Hugo Vankelecom, and Claude Libert. 2010. “Increased Glucocorticoid Receptor Expression and Activity Mediate the LPS Resistance of SPRET/EI Mice.” Journal of Biological Chemistry 285 (40): 31073–31086.
APA
Dejager, L., Pinheiro, I., Puimège, L., Fan, Y., Gremeaux, L., Vankelecom, H., & Libert, C. (2010). Increased glucocorticoid receptor expression and activity mediate the LPS resistance of SPRET/EI mice. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(40), 31073–31086.
Vancouver
1.
Dejager L, Pinheiro I, Puimège L, Fan Y, Gremeaux L, Vankelecom H, et al. Increased glucocorticoid receptor expression and activity mediate the LPS resistance of SPRET/EI mice. JOURNAL OF BIOLOGICAL CHEMISTRY. 2010;285(40):31073–86.
MLA
Dejager, Lien, Iris Pinheiro, Leen Puimège, et al. “Increased Glucocorticoid Receptor Expression and Activity Mediate the LPS Resistance of SPRET/EI Mice.” JOURNAL OF BIOLOGICAL CHEMISTRY 285.40 (2010): 31073–31086. Print.
@article{1060168,
  abstract     = {SPRET/Ei mice are extremely resistant to acute LPS-induced lethal inflammation when compared to C57BL/6. We found that in vivo SPRET/Ei mice exhibit strongly reduced expression levels of cytokines and chemokines. To investigate the role of the potent antiinflammatory glucocorticoid receptor (GR) in the SPRET/Ei phenotype, mice were treated with the GR antagonist RU486 or bilateral adrenalectomy. Under such conditions, both C57BL/6 and SPRET/Ei mice were strongly sensitized to LPS and the differences in LPS response between SPRET/Ei and C57BL/6 mice were completely gone. These results underscore the central role of GR in the LPS hyporesponsiveness of SPRET/Ei mice. Compared to C57BL/6, SPRET/Ei mice were found to express higher GR levels, which were reflected in increased GR transactivation. Using a backcross mapping strategy, we demonstrate that the high GR transcription levels are linked to the Nr3c1 (GR) locus on chromosome 18 itself. Unexpectedly, SPRET/Ei mice exhibit a basal overactivation of the hypothalamic-pituitary-adrenal axis, namely strongly increased corticosterone levels, ACTH levels and adrenocortical size. As a consequence of the excess of circulating glucocorticoids (GCs), levels of hepatic gluconeogenic enzymes are increased and insulin secretion from pancreatic β-cells is impaired, both of which result in hyperglycemia and glucose intolerance in SPRET/Ei mice. We conclude that SPRET/Ei mice are unique since they display an unusual combination of elevated GR expression and increased endogenous GC levels. Hence, these mice provide a new and powerful tool for the study of GR- and GC-mediated mechanisms, including immune repressive functions, neuroendocrine regulation, insulin secretion, and carbohydrate metabolism.},
  author       = {Dejager, Lien and Pinheiro, Iris and Puimège, Leen and Fan, Yedong and Gremeaux, Lies and Vankelecom, Hugo and Libert, Claude},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keywords     = {INSULIN,GENE,MOUSE,ENDOTOXIC-SHOCK,FEEDBACK-CONTROL,HORMONE-RECEPTORS,PANCREATIC BETA-CELLS,TUMOR-NECROSIS-FACTOR,MOLECULAR-MECHANISMS,FACTOR-KAPPA-B},
  language     = {eng},
  number       = {40},
  pages        = {31073--31086},
  title        = {Increased glucocorticoid receptor expression and activity mediate the LPS resistance of SPRET/EI mice},
  url          = {http://dx.doi.org/10.1074/jbc.M110.154484},
  volume       = {285},
  year         = {2010},
}

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